Thin-film micromesh for medical devices and related methods

ABSTRACT

Thin-film mesh for medical devices, including stent and scaffold devices, and related methods are provided. Micropatterned thin-film mesh, such as thin-film Nitinol (TFN) mesh, may be fabricated via sputter deposition on a micropatterned wafer. The thin-film mesh may include slits to be expanded into pores, and the expanded thin-film mesh used as a cover for a stent device. The stent device may include two stent modules that may be implanted at a bifurcated aneurysm such that one module passes through a medial surface of the other module. The thin-film mesh may include pores with complex, fractal, or fractal-like shapes. The thin-film mesh may be used as a scaffold for a scaffold device. The thin-film scaffold may be placed in a solution including structural protein such as fibrin, seeded with cells, and placed in the body to replace or repair tissue.

CROSS-REFERENCES TO RELATED APPLICATIONS

The present application is a divisional of U.S. patent application Ser.No. 15/615,698, filed on Jun. 6, 2017, which is a continuation ofInternational Application No. PCT/US2016/040864, filed on Jul. 1, 2016,which claims the benefit of U.S. Provisional Application No. 62/216,965,filed on Sep. 10, 2015, U.S. Provisional Application No. 62/209,185,filed on Aug. 24, 2015, U.S. Provisional Application No. 62/209,254,filed on Aug. 24, 2015, and U.S. Provisional Application No. 62/188,218,filed on Jul. 2, 2015, which are hereby incorporated by reference intheir entirety.

TECHNICAL FIELD

The present disclosure generally relates to medical devices and, moreparticularly, to thin-film micromeshes for medical devices and relatedmethods.

BACKGROUND

Aneurysms in blood vessels are relatively common in aging patients. Thecorresponding blood vessel may rapidly hemorrhage, perhaps mortally, ifsuch aneurysms rupture. Given the extreme health risk, stent devices,such as flow diverter stents, have been developed to treat aneurysms. Aconventional stent typically is a braided wire device that is compressedand delivered using a catheter and guide wire to the desired location.The braided wire device diverts blood flow such that the pressure on theaneurysm is significantly reduced, blood flow in the aneurysm sac isdiminished so that it occludes, and the aneurysm thereby no longer posesimminent danger of rupture to the patient.

A known complication of conventional stent devices is the phenomenon ofdelayed aneurysm rupture. This occurs when a patient is seeminglysuccessfully treated with a stent device, but weeks or months later theaneurysm bursts, causing hemorrhagic stroke and death. Accordingly,there is a need in the art for improved stent devices that reduce therate of delayed aneurysm rupture and achieve higher occlusion rates.

In tissue engineering, cells are often implanted or seeded intoscaffolds, such as cell scaffolds, that support growth of athree-dimensional tissue. Conventional scaffolds are typically madeusing hydrogels, fibrin-based gels, extracellular matrix components, andelectrospun polymers. A significant problem in tissue engineering isfabrication and design of scaffolds that facilitate confluent, healthycellular growth in a controlled manner (e.g., can adopt a desiredthree-dimensional conformation), facilitate cell to cell interactions sothat nutrient and information exchange can occur, and provide mechanicalintegrity so that they can withstand physiologic stress without fractureor some other form of mechanical compromise.

Conventional scaffolds are either too brittle or too malleable, andsuffer from the inability to engineer exact pore configurations giventhat they rely on a random distribution of pores. Conventional scaffoldsthus fail to achieve the desired conformation, strength, and controlledporosity. Accordingly, there is a need in the art for improved scaffoldsthat can achieve the desired conformation, strength, and controlledporosity.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1A is a diagrammatic top plan view of a portion of a thin-filmmicromesh before expansion according to an embodiment.

FIG. 1B is a diagrammatic top plan views of a portion of a thin-filmmicromesh after expansion according to an embodiment.

FIG. 1C is a diagrammatic side elevational view of a thin-film micromeshdevice according to an embodiment.

FIG. 1D is a diagrammatic cross-sectional view of a blood vessel with ananeurysm in which a thin-film micromesh device is placed according to anembodiment.

FIGS. 2A-B are close-up images of a portion of a thin-film micromeshaccording to an embodiment.

FIG. 2C is a close-up image of a portion of a thin-film micromesh afterexposure to whole blood according to an embodiment.

FIG. 2D is an image of a thin-film micromesh device according to anembodiment.

FIG. 3 is a flow diagram of a process to fabricate a thin-film micromeshfor a medical device according to an embodiment.

FIGS. 4A-Q are diagrammatic cross-sectional views of layers being formedon a substrate to fabricate a thin-film micromesh according to anembodiment.

FIGS. 5A-H are diagrammatic top plan views of layers being formed on asubstrate to fabricate a thin-film micromesh according to an embodiment.

FIGS. 6A-B illustrate thin-film micromesh fenestration designs that havethe same porosity but different pore densities according to one or moreembodiments.

FIGS. 7A-C are diagrammatic top plan views of portions of thin-filmmicromeshes with different percent metal coverages (PMC) and poredensities according to one or more embodiments.

FIGS. 8A-B illustrate a fenestration of a thin-film micromesh before andafter expansion according to an embodiment.

FIGS. 9A-C are graphs characterizing thin-film micromeshes according toone or more embodiments.

FIG. 10A is a diagrammatic top plan view of a portion of a variableporosity thin-film micromesh according to an embodiment.

FIG. 10B is a diagrammatic top plan view of a portion of a variableporosity thin-film micromesh after expansion according to an embodiment.

FIG. 10C is a diagrammatic side elevational view of a variable porositythin-film micromesh device with an intermediate higher pore densityregion flanked by lower pore density regions on both sides according toan embodiment.

FIG. 10D is a diagrammatic side elevational view of a variable porositythin-film micromesh device with a higher pore density region on one sideand a lower pore density on the other side according to an embodiment.

FIG. 10E is a diagrammatic cross-sectional view of a blood vessel withan aneurysm in which a variable porosity thin-film micromesh device isinserted according to an embodiment.

FIG. 11A is a diagrammatic top plan view of a thin-film micromesh withone or more attachment points or areas before expansion according to anembodiment.

FIG. 11B is a diagrammatic top plan view of a thin-film micromesh withone or more attachment points/areas after expansion according to anembodiment.

FIG. 11C is a diagrammatic side elevational view of a thin-filmmicromesh with attachment points/areas on one end staggered fromattachment points/areas on an opposing end according to an embodiment.

FIGS. 11D-E are diagrammatic top plan views of layers of thin-filmmicromesh that join at the edges to form the thin-film micromesh of FIG.11C when expanded to its three-dimensional form according to anembodiment.

FIG. 11F is a diagrammatic side elevational view of a thin-film meshdevice including a thin-film micromesh attached to a backbone at one ormore attachment points/areas according to an embodiment.

FIG. 11G is a diagrammatic side elevational view of a thin-film meshdevice that is bent in which a thin-film micromesh is held in place byattachment points/areas according to an embodiment.

FIGS. 12A-B are diagrammatic close-up views of an attachment point/areawith holes according to an embodiment.

FIGS. 12C-D are diagrammatic close-up views of an attachment point/areawith a wrapping area according to an embodiment.

FIGS. 13A-B are diagrammatic flat-pattern views of portions ofkink-resistant stent backbones including V-shaped/heart-shapedfenestrations according to one or more embodiments.

FIG. 14 is a flow diagram of a process to implant a modular thin-filmmicromesh stent at a bifurcated aneurysm site according to anembodiment.

FIGS. 15A-C are diagrammatic cross-sectional views of a bifurcatedaneurysm site in which a modular thin-film micromesh stent is implantedaccording to an embodiment.

FIGS. 16A-E illustrate shapes that may be implemented as pore edges orpore shapes of a thin-film micromesh according to one or moreembodiments.

FIG. 17 is a flow diagram of a process to fabricate a thin-filmmicromesh for a medical device for a tissue-engineering according to oneor more embodiments.

FIG. 18 is a diagrammatic perspective view of a multi-layered thin-filmmicromesh membrane for a tissue engineered vascular graft (TEVG)according to an embodiment.

FIG. 19A is a diagrammatic top plan view of a double-spiral thin-filmmicromesh membrane according to an embodiment.

FIG. 19B is a diagrammatic perspective view of a three-dimensionaldouble-spiral thin-film micromesh structure according to an embodiment.

FIG. 20A is a diagrammatic top plan view of a honeycomb thin-filmmicromesh membrane according to an embodiment.

FIG. 20B is a diagrammatic perspective view of a three-dimensionalhoneycomb thin-film micromesh structure according to an embodiment.

FIG. 21 is a diagrammatic top plan view of an equilateral-trianglethin-film micromesh membrane according to an embodiment.

FIG. 22 is a diagrammatic top plan view of an overlapping-circlethin-film micromesh membrane according to an embodiment.

FIGS. 23A-B are diagrammatic top plan views of an amplifier thin-filmmicromesh membrane that is denser on one side/area according to anembodiment.

Embodiments of the present disclosure and their advantages are bestunderstood by referring to the detailed description that follows. Itshould be appreciated that like reference numerals are used to identifylike elements illustrated in one or more of the figures, in which theshowings therein are for purposes of illustrating the embodiments andnot for purposes of limiting them.

DETAILED DESCRIPTION

Thin-film micromeshes (also referred to as thin-film meshes) for medicaldevices (e.g., stent devices and scaffold devices) and related methodsare provided. As used herein, a thin-film mesh is defined to be lessthan 100 μm (micrometers or microns) in thickness. In variousembodiments, a thin-film mesh is formed using fenestrated thin-filmNitinol (TFN), although other thin-film mesh materials may be used toform the thin-film mesh disclosed herein. The following discussion isthus directed to TFN meshes without loss of generality.

FIGS. 1A-D show a thin-film mesh 100, 110 and a thin-film mesh device120, a medical device including thin-film mesh 110. FIG. 1A is adiagrammatic top plan view of a portion of thin-film mesh 100 with slits102 (e.g., closed fenestrations) prior to expansion. Thin-film mesh 100may be expanded along axis 104, which may be referred to as axis ofexpansion 104, to open up slits/fenestrations 102 oriented perpendicularto axis 104 and parallel to axis 106, which may be referred to as slitaxis 106, by extending thin-film mesh 100 in directions 108 to formthin-film mesh 110 in FIG. 1B and FIG. 1C.

Each of slits/fenestrations 102 may have a slit length of between 25 μmand 500 μm. The slit length may be modulated based on the type ofmedical device, the type of medical treatment, the body region beingtreated, and/or the type of aneurysm being treated. For example, theslit length of thin-film mesh 100/110 may be between 50 μm and 300 μm(e.g., between 50 μm and 225 μm, or between 50 μm and 200 μm) to providethin-film mesh device 120 with advantageous features such as fibrindeposition and cell growth (e.g., endothelialization) when placed in ablood vessel.

The ability of thin-film mesh 100/110 to effectively expand along axis104 may depend on the length of slits 102. Slits 102 with a longer slitlength will result in thin-film mesh 100/110 with increased ability forexpansion, while slits 102 with a shorter slit length will result inthin-film mesh 100/110 with a decreased ability for expansion.

FIG. 1B is a diagrammatic top plan view of a portion of thin-film mesh110 including pores 112 (e.g., open fenestrations) after expansion.Thin-film mesh 110 may be formed by expanding thin-film mesh 100 in FIG.1A. The expansion may extend thin-film mesh 100 along axis 104 such thatthere is a large increase in length along axis 104 but a small change(e.g., a small decrease) in length along axis 106. In some embodiments,the expansion may extend thin-film mesh 100 along axis 104 in a rangefrom 50% to 800%.

When expanded, slits/fenestrations 102 in FIG. 1A open up intopores/fenestrations 112 to form a “chain-link” fence pattern, such asdiamond-shaped pores/fenestrations. Thin-film mesh 110 forms strutsaround each diamond-shaped pore/fenestration 112. Alternatively,thin-film mesh 110 may be directly formed with diamond-shaped pores 112(e.g., in its final configuration or partially opened). It will beappreciated that other pore/fenestration shapes may be used in otherembodiments.

In one or more embodiments, thin-film mesh 110 has a pore density(fenestrations per square mm) of between 15 pores/mm² and 2217pores/mm², and a percent metal coverage (PMC) of between 6% and 83%. Insome embodiments, thin film mesh 110 has a high pore density (e.g., 50pores/mm²-3000 pores/mm²) and a low metal coverage (e.g., 10%-35%),which may advantageously promote a planar deposition of fibrin followedby rapid cell growth (e.g., endothelialization).

Thin-film mesh 110 may be formed, for example, as a thin-film mesh coverfor a stent backbone (e.g., backbone 122 in FIG. 1C and FIG. 2D) or as athin-film mesh scaffold for tissue engineering (e.g., as described belowin relation to FIG. 17 ). Thin-film mesh 110 may otherwise be includedin a medical device for its advantageous properties as further describedherein.

FIG. 1C is a diagrammatic side elevational view of thin-film mesh device120 that includes thin-film mesh 110 and a backbone 122 (e.g., a stentbackbone). Thin-film mesh 110 expanded to its three-dimensional form(e.g., a cylindrical tube or other shape) may be assembled over backbone122, which provides structural support for thin-film mesh 110 whilemaintaining the advantageous features of thin-film mesh 110, such asfibrin deposition and cell growth (e.g., endothelialization) when placedin a blood vessel.

In one or more embodiments, thin-film mesh 100/110 is fabricated as aplurality of layers of thin-film on a substrate such as a silicon waferusing silicon wafer micromachining technology, as described below inrelation to FIG. 3 , FIGS. 4A-Q, and FIGS. 5A-H. For example, two layersof thin-film may be joined at the two edges either along axis 106 oralong axis 104 such that thin-film mesh 100 expands to thin-film mesh110 formed as a cylindrical tube as shown in FIG. 1C, FIG. 2D, and 5H.Thin-film mesh 100/110 joined at the two edges along axis 104 and athin-film covered stent that includes a stent backbone and thin-filmmesh 100/110 with axis of expansion 104 oriented parallel to thelongitudinal axis of the stent backbone are further described inInternational Application No. PCT/US2016/39436, filed on Jun. 24, 2016,which claims the benefit of U.S. Provisional Application No. 62/185,513,filed on Jun. 26, 2015, U.S. Provisional Application No. 62/188,218,filed on Jul. 2, 2015, U.S. Provisional Application No. 62/209,185,filed on Aug. 24, 2015, U.S. Provisional Application No. 62/209,254,filed on Aug. 24, 2015, and U.S. Provisional Application No. 62/216,965,filed on Sep. 10, 2015. International Application No. PCT/US2016/39436and U.S. Provisional Application No. 62/185,513 are hereby incorporatedby reference in their entirety.

FIG. 1D shows a diagrammatic cross-sectional view of a blood vessel 132with an aneurysm 134 and a branch vessel 136 (e.g., a branch artery) inwhich thin-film mesh device 120 of FIG. 1C is implanted. Thin-film meshdevice 120 may advantageously be used as a flow diverter due to theproperties of thin-film mesh 110. Flow diverters must strike a balancebetween diverting flow from an aneurysm sac while permitting flow in anyperianeurysmal branch vessels. Thin-film mesh 110 advantageously divertsblood flow into aneurysm 134 and promotes rapid deposition of fibrin andendothelialization at a neck 138 of aneurysm 134 so that aneurysm 134 isoccluded, while at the same time allowing blood flow through branchvessel 136.

Thin-film mesh device 120 advantageously has a reduced rate of delayedaneurysm rupture when compared to conventional flow diverters.Conventional wire flow diverter stents may provide occlusion of aneurysmnecks, but because the pores of such devices are often filled withparticles made up of blood coagulation products, inflammatory cells, andcellular debris, such particles may be dislodged and cause delayedaneurysm rupture. Indeed, endothelialization is slow to occur and isoften partial at best in conventional wire flow diverter stents. Incontrast, thin-film mesh 110 provides a structure on which the bloodvessel walls are rapidly rebuilt through endothelialization, promoting ahealthy and stable cellular lining, and because the cellular lining isnot prone to dislodging as particles of blood coagulation products andthe like, the rate of delayed aneurysm rupture is significantly reduced.

FIG. 2A is a close-up image of a portion of an example thin-film mesh110 that has a pore density of 70 pores/mm² and a percent metal coverageof 20% before exposure to fibrin. In this example, pores/fenestrations112 of thin-film mesh 110 has a pore size of 240 μm to 300 μm.

FIG. 2B is a close-up image of a portion of an example thin-film mesh110 and portions of pores/fenestrations 112. Conventional flow diverterstents made with wire meshes are not flat where the wires intertwine. Incontrast, because thin-film mesh 110 is made with a layer of materialsuch as Nitinol and expanded, there is no intertwining of wires. Thus,thin-film mesh 110 is flat all around its pores 112 as shown in FIG. 2B,which is advantageous for promoting rapid deposition of fibrin and cellgrowth (e.g., endothelialization).

FIG. 2C is a close-up image of a portion of an example thin-film mesh110 after exposure to fibrin. The fibrin mat facilitates cell growth,and other biomolecules may be incorporated into thin-film mesh 110. Insome embodiments, thin-film mesh 110 may advantageously be used as astent cover for a stent device, as the rapid deposition of fibrin andcell growth (e.g., endothelialization) not only occludes aneurysms butalso promotes healing of the blood vessels. In other embodiments,thin-film mesh 110 may advantageously be used as a scaffold (e.g., amembrane or other scaffold structure) for a scaffold device in tissueengineering, as thin-film mesh 110 may be formed having the desiredconformation, strength, and controlled porosity. In further embodiments,thin-film mesh 110 may advantageously be included in medical devicesthat would benefit from planar deposition of fibrin followed by rapidcell growth (e.g., endothelialization) or the ability to be formed withthe desired conformation, strength, and controlled porosity.

FIG. 2D shows a side elevational view image of an example thin-film meshdevice 120 including backbone 122 and thin-film mesh 110. In someembodiments, thin-film mesh 110 forms a cylindrical tube and may beassembled on backbone 122 by placing thin-film mesh 110 over backbone122 such that thin-film mesh 110 wraps around backbone 122.Alternatively, thin-film mesh 110 may be attached to the interiorsurface of backbone 122.

In some embodiments, thin-film mesh 110 includes one or more attachmentpoints or areas that are attached to backbone 122. Radiopaque markersmay be used to affix thin-film mesh 110 to stent backbone 122. Examplesof attachment points/areas of thin-film mesh 110 and the use ofradiopaque markers are further described below in relation to FIGS.12A-D.

Backbone 122 may be a wire backbone made of metal (e.g., a metal alloy)or a laser-cut backbone fabricated from a metal hypotube. Alternatively,backbone 122 may be a bioabsorbable backbone composed of a bioabsorbablemetal or polymeric material that is absorbed, degraded, dissolved, orotherwise fully broken down after a predetermined amount of time (e.g.,3-6 months, 6-24 months, etc.) after implantation in a patient whilethin-film mesh 110 remains in the patient. Thin-film mesh device 120with such bioabsorbable backbone 122 may have advantages compared tomedical devices that use a backbone that is not absorbed or does notdegrade, which presents potential dangers and risks. For example,long-term presence of a backbone is potentially dangerous because itcould serve as a continuing risk for thrombotic complications. Further,the backbone may exert a mechanical force on a parent artery thatchanges its compliance and flexibility in a manner that may alsoincrease the likelihood of parent artery stenosis. Advantageously,thin-film medical device 120 with bioabsorbable backbone 122 deliversthin-film mesh 110 to a target site (e.g., an aneurysms or arterialdisease) while bioabsorbable backbone 122 degrades or is absorbed. Forexample, bioabsorbable backbone 122 may provide structural support forthin-film mesh 110 while maintaining the advantageous features ofthin-film mesh 110, such as fibrin deposition and cell growth (e.g.,endothelialization) when placed at the target site such as a bloodvessel with an aneurysm. By the time bioabsorbable backbone 122degrades, the blood vessel may have fully healed and no longer requirethe mechanical support provided by bioabsorbable backbone 122. Inanother example, bioabsorbable backbone 122 may simply be a means todeliver thin-film mesh 110 to a target site and not play a major role inaneurysm occlusion and healing of the aneurysm neck region. It will beappreciated that other material or structure may be used for backbone122 in alternative embodiments.

FIG. 3 is a flow diagram of a process 300 to fabricate a thin-film mesh,such as thin-film mesh 100/110 of FIGS. 1A-D or FIGS. 2A-D, for athin-film mesh device, such as thin-film mesh device 120 of FIGS. 1C-Dand FIG. 2D. At block 302, trenches are formed on a wafer 400 (e.g., asilicon wafer or other wafer) as shown in FIGS. 4A-4E and 5A-5C. FIGS.4A and 5A show wafer 400, which may have an oxide layer with a thicknessof between 500 nm and 1 μm on top. A photoresist 402 is spun-coated onwafer 400 as shown in FIG. 4B. By patterning and developing photoresist402 using photolithography, a pattern of exposed areas 404 is formed asshown in FIG. 4C and FIG. 5B. The pattern of exposed areas 404 isavailable for etching. Deep reactive ion etching (DRIE) is performed toform grooves or trenches 406 that are at least 15 μm deep (e.g., between25 μm and 200 μm deep) as shown in FIG. 4D. Photoresist 402 is removedand wafer 400 is cleaned, resulting in etched wafer 400 with trenches406 as shown in FIG. 4E and FIG. 5C. Trenches 406 may form amicropattern that provides a template for thin-film mesh 100. Theresolution of the micropattern using the DRIE process may be, forexample, approximately 1 μm. Although two micropatterns 502 for twothin-film meshes are shown in FIG. 5C, wafer 400 may include moremicropatterns. The term “approximately,” as used herein when referringto a measurable value, encompasses variations of ±20%, ±10%, ±5%, ±1%,±0.5%, or ±0.1% of the value.

At block 304, a sacrificial layer 408 (e.g., a chrome sacrificial layeror a copper sacrificial layer), also referred to as a lift-off layer, isdeposited as shown in FIG. 4F. Sacrificial layer 408 may be deposited bysputter deposition or evaporation deposition such as electron beamphysical vapor deposition (EBPVD). Sacrificial layer 408 may have athickness of, for example, 1 μm or less (e.g., approximately 500 nm).

At block 306, a Nitinol layer 410 is deposited as shown in FIG. 4G andFIG. 5D. Nitinol layer 410 may have a thickness of, for example, between1 μm and 20 μm (e.g., approximately 5 μm). As sputtered Nitinol atregions corresponding to trenches 406 fall to the bottom of trenches406, the micropattern of trenches 406 of wafer 400 are duplicated onNitinol layer 410 as corresponding fenestrations (e.g., closedfenestrations) such as slits 102 of thin-film mesh 100 as shown in FIG.1A. The resulting pattern of fenestrations 102 may also be denoted as afiche in that fenestrations 102 are in closed form prior to an expansionof thin-film mesh 100. Just like a microfiche, each fiche or pattern offenestrations 102 effectively codes for resulting fenestrations 112 whenthin-film mesh 100 is expanded to fully open up fenestrations 102.

At block 308, a shadow mask 412 is applied as shown in FIG. 4H. Shadowmask 412 is applied to a mesh region 414 and exposes seam regions 416for deposition of a bonding layer 418.

At block 310, bonding layer 418 (e.g., an aluminum bonding layer) isdeposited as shown in FIG. 4I. Bonding layer 418 may have a thicknessof, for example, 1 μm or less (e.g., approximately 500 nm).

At block 312, shadow mask 412 is removed as shown in FIG. 4J.

At block 314, a shadow mask 420 is applied as shown in FIG. 4K. Shadowmask 420 is applied to seam regions 416 and exposes mesh region 414 fordeposition of a sacrificial layer 422.

At block 316, sacrificial layer 422 (e.g., a chrome sacrificial layer ora copper sacrificial layer) is deposited as shown in FIG. 4L and FIG.5E. Sacrificial layer 422 may have a thickness of, for example, 1 μm orless (e.g., approximately 500 nm).

At block 318, shadow mask 420 is removed as shown in FIG. 4M.

At block 320, a Nitinol layer 424 is deposited as shown in FIG. 4N andFIG. 5F. Nitinol layer 424 may have a thickness of, for example, between1 μm and 50 μm (e.g., approximately 5 μm). Similarly to block 306, assputtered Nitinol at regions corresponding to trenches 406 fall to thebottom of trenches 406, the micropattern of trenches 406 of wafer 400are duplicated on Nitinol layer 424 as corresponding fenestrations(e.g., closed fenestrations) such as slits 102 of thin-film mesh 100 asshown in FIG. 1A.

At block 322, a protective layer 426 (e.g., a protective chrome layer)is deposited as shown in FIG. 4O. Protective layer 426 may have athickness of, for example, 1 μm or less (e.g., approximately 500 nm).

At block 324, Nitinol layers 410, 424 and bonding layer 418 are annealedto form thin-film mesh 100 as shown in FIG. 4P. Wafer 400 with Nitinollayers 410, 424 and bonding layer 414 may be annealed at a hightemperature (e.g., approximately 675° C. for approximately 10 minutes)to melt bonding layer 418 and crystalize amorphous Nitinol layers 410,424. Nitinol layer 410 and Nitinol layer 424 are fused in inseam region416.

At block 326, thin-film mesh 100 is released as shown in FIG. 4Q andFIG. 5G. Annealed wafer 400 may be placed in chrome etchant (e.g., forapproximately 1 hour) to release thin-film mesh 100 from top of thewafer 400.

At block 328, thin-film mesh 100 is expanded to form a three-dimensionalthin-film mesh 110 with fenestrations 112 that have been opened up suchas a cylindrical tube as shown in FIG. 5H. It will be appreciated thatcombining the lift-off process with multiple-layer depositions ofNitinol separated by layers of sacrificial layers enables fabrication ofthin-film meshes 110 of various other three-dimensional shapes in otherembodiments. Further descriptions and examples of fenestrated TFN andthree-dimensional fabrication techniques are disclosed in InternationalApplication No. PCT/US2014/61836, filed Oct. 22, 2014, which claims thebenefit of U.S. Provisional Application No. 61/894,826, filed Oct. 28,2013, and U.S. Provisional Application No. 61/148,689, filed Apr. 17,2015, which are hereby incorporated by reference in their entirety.

FIGS. 6A-B illustrate thin-film mesh fenestration designs that have thesame porosity but different pore densities. The primary characteristicsthat determine the degree of flow diversion are percent metal coverage(PMC) and pore density, where higher percent metal coverage and higherpore density yield an increased flow diverting effect. Percent metalcoverage is the fraction of the area of metal over the total area.Porosity is the fraction of the open area over the total area.Accordingly, for expanded thin-film mesh 110, the porosity (inpercentage) and percent metal coverage of thin-film mesh 110 add up to100%. Similarly, for thin-film mesh device 120, the porosity ofthin-film mesh device 120 (in percentage), the percent metal coverage ofthin-film mesh 110, and the percent metal coverage of backbone 122 addup to 100%.

The surface shown in FIG. 6A has a length 602 of 1 mm and a pore length604 of 0.71 mm, such that the surface has a porosity of 50%, a poredensity of 1 pore/mm², and a total edge length of 2.84 mm. The surfaceshown in FIG. 6B has a length 602 of 1 mm and a pore length 606 of 0.24mm, such that the surface has a porosity of 50%, a pore density of 9pore/mm², and a total edge length of 8.64 mm. Even though the poredesigns of FIG. 6A and FIG. 6B have the same porosity of 50%, the designin FIG. 6A has a pore density of 1 pore/area while the design in FIG. 6Bhas a pore density of 9 pores/area. For flow diverter stents, two flowdiverter stents having similar porosity and percent metal coverage mayhave drastically different efficacy due to different pore density. Forexample, thin-film mesh device 120 with a percent metal coverage of10-15% and 50-100 pores/mm² are more effective compared to aconventional flow diverter stent having a percent metal coverage of 35%and 14 pores/mm². Thin-film mesh device 120 with a percent metalcoverage of 25-35% and 150-250 pores/mm² are even more effectivecompared to conventional flow diverter stents having a percent metalcoverage of 35% and 14 pores/mm² because the increased pore densityprovides more friction per unit area and provides a surface for fibrindeposition and cell growth (e.g., endothelialization).

FIGS. 7A-C are diagrammatic top plan views of portions of thin-filmmeshes 110 with different percent metal coverages (PMC) and poredensities. As shown in FIG. 7A, thin-film mesh 110 has a percent metalcoverage of 12.8%, a pore density of 70 pores/mm², and a pore size of300 μm. As shown in FIG. 7B, thin-film mesh 110 has a percent metalcoverage of 15.3%, 100 pores/mm², and a pore size of 225 As shown inFIG. 7C, thin-film mesh 110 has a percent metal coverage of 25.2%, 175pores/mm², and a pore size of 100 In some embodiments, thin-film mesh110 may have a percent metal coverage of between 17% and 66% and a poredensity of between 16 pores/mm² and 1075 pores/mm². In otherembodiments, thin-film mesh 110 may have a percent metal coverage of19-47% and a pore density of 81 pores/mm² and 424 pores/mm². It will beappreciated that other percent metal coverage and pore density amountsmay be used in further embodiments.

FIGS. 8A-B illustrate fenestration 112 of thin-film mesh 100 before andafter expansion. FIG. 8A illustrates slit 102 (e.g., a closedfenestration) and a surrounding struts 116 of thin-film mesh 110 beforeexpansion. Surrounding struts 116 may have a strut width 802, which maybe between 1 and 25 μm. Slit 102 may have a slit width 804 and a slitlength 114. One half of slit width may be referred to as Y₁, and onehalf of slit length 114 may be referred to as X₁.

FIG. 8B illustrates pore 112 (e.g., an open fenestration) andsurrounding strut 116 of thin-film mesh 110 after expansion. Surroundingstrut 116 may have a strut width 802, which may be between 1 and 25 μm.Diamond-shaped pore 112 may have a short diagonal length 814 along shortdiagonal axis such as axis 104 of FIGS. 1A-B, a long diagonal length 816along long diagonal axis such as axis 106 of FIGS. 1A-B, and a sidelength 820. Diamond-shaped pore 112 may further have a strut angle θ818. In some embodiments, strut angle θ 818 may be between 30 and 90degrees. Length 824, which is one half of short diagonal length 814, maybe referred to as Y₂, and length 826, which is one half of long diagonalaxis 816, may be referred to as X₂.

As side length 820 is equal or approximately equal to half of slitlength 114 in FIG. 8A (given that pore 112 open up from slit 102), sidelength 820 may equal or be approximated as X₁. The lengths X₁, X₂, andY₂, and strut angle θ may be related by the following equations:

${{\cos\frac{\theta}{2}} = \frac{X_{2}}{X_{1}}}{{\sin\frac{\theta}{2}} = \frac{Y_{2}}{X_{1}}}$

Accordingly, a percentage change in X (along axis 106) and a percentagechange in Y (along axis 104) may be calculated. For example, if slitlength 114 is 150 μm and slit width 804 is 10 μm, and strut angle θ 818is 45°, then: X₁=75 μm, Y₁=5 μm, X₂=69.3 μm, and Y₂=28.7 μm. The percentchange in X is small, −7.6%, when compared to the percent change in Y,474%.

Further, other features of diamond-shaped pores 112 may be determined bythe following equations:

${{Pore}{area}{= {2X_{2}Y_{2}}}}{{{Pore}{area}{with}{strut}{metal}} = {2\left( {X_{2} + W} \right)\left( {Y_{2} + W} \right)}}{{{Pore}{density}} = \frac{1}{2\left( {X_{2} + W} \right)\left( {Y_{2} + W} \right)}}{{{Percent}{metal}{coverage}} = {1 - {\frac{2X_{2}Y_{2}}{2\left( {X_{2} + W} \right)\left( {Y_{2} + W} \right)}.}}}$

For example, if slit length 114 is 150 μm, slit width 804 is 10 μm,strut width 802 is 8 μm, and strut angle θ 818 is 30°, then: X₁=75 μm,Y₁=5 μm, X₂=72 μm, Y₂=19 μm, pore area=0.0027 mm², pore area with strutmetal=0.0043 mm², pore density=230 pores/mm², and percent metalcoverage=37%.

FIGS. 9A-C are graphs characterizing thin-film meshes 110. FIG. 9A showsa graph of pore density vs. slit length 114, assuming an 8 μm strutwidth. FIG. 9B shows a graph of percent metal coverage vs. slit length114, assuming an 8 μm strut width. FIG. 9C shows a graph of edge densityvs. slit length 114, assuming an 8 μm strut width. The ranges ofphysical characteristics—slit length 114, pore density, percent metalcoverage, and edge density—with advantageous properties including rapidfibrin deposition and cell growth (e.g., endothelialization) are shownas 902, 904, and 906 in FIGS. 9A-C.

In some embodiments, thin-film mesh 110 has a slit length shown in FIGS.9A-C, where any value may form an upper end point or a lower end point,as appropriate. Thin-film mesh 110 may have a pore density shown in FIG.9A, where any value may form an upper end point or a lower end point, asappropriate. Thin-film mesh 110 may also have a percent metal coverageshown in FIG. 9B, where any value may form an upper end point or a lowerend point, as appropriate. Further, thin-film mesh 110 may have an edgedensity shown in FIG. 9C, where any value may form an upper end point ora lower end point, as appropriate.

In an example, thin-film mesh 110 has a slit length between 50 μm and225 μm. Thin-film mesh has a pore density corresponding to a slit lengthof between 50 μm and 225 μm shown in FIG. 9A (as indicated by 902).Thin-film mesh 110 also has a percent metal coverage corresponding to aslit length of between 50 μm and 225 μm shown in FIG. 9B (as indicatedby 904). Thin-film mesh 110 has an edge density corresponding to a slitlength of between 50 μm and 225 μm shown in FIG. 9C (as indicated by906).

In another example, thin-film mesh 110 has a slit length between 100 μmand 150 μm. Thin-film mesh has a pore density corresponding to a slitlength of between 100 μm and 150 μm shown in FIG. 9A. Thin-film mesh 110also has a percent metal coverage corresponding to a slit length ofbetween 100 μm and 150 μm shown in FIG. 9B. Thin-film mesh 110 has anedge density corresponding to a slit length of between 100 μm and 150 μmshown in FIG. 9C.

FIGS. 10A-E show a variable porosity thin-film mesh 1000, 1010 and avariable porosity thin-film mesh device 1020. FIG. 10A is a diagrammatictop plan view of a portion of variable porosity thin-film mesh 1000 withslits 1012, 1014 (e.g., closed fenestrations) prior to expansion.Variable porosity thin-film mesh 1000 includes at least one region 1002with a density of slits 1012 that is higher than a density of slits 1014in at least one other region 1004. Slits 1012 in region 1002 may besmaller than slits 1014 in region 1004.

When thin-film mesh 1000 is fabricated, Nitinol layers 410 and 424 inFIGS. 4G and 4N may be deposited in a shape that is wider in higher poredensity region 1002 than low pore density region 1004 to account forless expansion in higher pore density region 1002. For example,thin-film mesh 1000 may be wider in middle region 1002 where poredensity is higher than side regions 1004 where pore density is lower.

FIG. 10B is a diagrammatic top plan view of a portion of variableporosity thin-film mesh 1010 including pores 1016, 1018 (e.g., openfenestrations) after expansion. Variable thin-film mesh 1000 in FIG. 10Amay be expanded in directions 1006 such that slits/fenestrations 1012and 1014 open up to pores 1016 and 1018 to form a “chain-link” fencepattern with a variable pore density and percent metal coverage along anaxis 1008, which may be referred to as axis of variable porosity 1008.In some embodiments, the expansion may extend thin-film mesh 1000 in arange from 50% to 800%. It will be appreciated that otherpore/fenestration shapes may be used in alternative embodiments.

Variable porosity thin-film mesh 1010 may include at least one region1002 with a density of pores 1016 that is higher than a density of pores1018 in at least one other region 1004. The pore density of thin-filmmesh 1010 may vary along axis of variable porosity 1008. Pores 1016 inhigh pore density region 1002 may be smaller than pores 1018 in low poredensity region 1004.

FIGS. 10C and 10D are diagrammatic side elevational views of thin-filmmesh devices 1020 that include thin-film meshes 1010 assembled onbackbones 122. Thin-film mesh 1010 may have a pore density that variesalong the longitudinal length of backbone 112, and axis 1008 may furtherbe referred to as long/longitudinal axis 1008 of backbone 112. In someembodiments, thin-film mesh device 1020 includes high pore densityregion 1002 and low pore density regions 1004 flanking both sides ofregion 1002 as shown in FIG. 10C. In other embodiments, thin-film meshdevice 1020 includes region 1002 on one side and region 1004 on theother side of thin-film mesh device 1020 as shown in FIG. 10D.

FIG. 10E is a diagrammatic cross-sectional view of blood vessel 132 withaneurysm 134 and branch vessel 136 in which thin-film mesh device 1020of FIG. 10C is inserted. Thin-film mesh device 1020 may be placed suchthat high pore density region 1002 is at aneurysm neck region 138, andlow pore density region 1004 is at or near branch vessels 136.Advantageously, a higher pore density and higher percent metal coveragemay be achieved at aneurysm neck 138 by placing high pore density region1002 at aneurysm neck 138, thereby reducing blood flow from flowing intothe aneurysm, such as intra-aneurysmal flow, and promote faster healingand more robust scaffold for parent artery reconstruction andendothelialization. Further, a low pore density and low percent metalcoverage may be achieved at nearby branch vessels 136 by placing lowpore density region 1004 at regions other than aneurysm neck 138,thereby facilitating vessel healing while allowing better blood flowthrough branch arteries and, thus, making the device safer for patients.In some embodiments, thin-film mesh device 1020 may include one or moreradiopaque markers 1048 that delineate the transition zone betweenregion 1002 and region 1004. In other embodiments, the variation in poredensity may be gradual such that there is no transition zone, in whichcase radiopaque markers 1048 (e.g., gold markers) may be positionedrelative to an area having a higher pore density. In furtherembodiments, thin-film mesh 1010 may only include high pore densityregion 1002 that is placed over a defined portion of stent 122 (e.g., inthe middle or on one side) and forego low pore density region 1004altogether.

FIGS. 11A-G show thin-film meshes 1100, 1110 and thin-film mesh devices1120 including one or more attachment points/areas 1102. FIG. 11A is adiagrammatic top plan view of thin-film mesh 1100 prior to expansionthat includes one or more attachment points/areas 1102 at the end ofnarrowing regions 1104 (e.g., having triangular shapes) and a region1106 with pores/fenestrations 1108. Thin-film mesh 1100 may have a widthof, for example, between approximately 25 μm and 50 μm prior toexpansion. Fenestrations 1108 may be provided at narrowing regions 1104(not shown) with the same pore density as region 1106 or avarying/graduated pore density. Each of attachment points/areas 1102 areconfigured to be attached to a backbone or a scaffold such as backbone122 in FIGS. 1C-D and 2D. Examples of attachment points/areas 1102 areshown in FIGS. 12A-B and 13A-B.

FIG. 11B is a diagrammatic top plan view of thin-film mesh 1110 afterexpansion. Thin-film mesh 1110 may be formed by expanding thin-film mesh1100. Thin-film mesh 1110 may have a width of, for example, betweenapproximately 50 μm and 400 μm after expansion. The angle at attachmentpoint/area 1102 of thin-film mesh 1110 after expansion may be largerthan the angle at attachment point/area 1102 of thin-film mesh 1100prior to expansion.

FIG. 11C shows a side elevational view of thin-film mesh 1110 expandedto its three-dimensional form with attachment points/areas on one endstaggered from attachment points/areas on an opposing end. Thin-filmmesh 1110 may include two attachment points 1102 at one end and twoadditional attachment points 1102 at the opposing end. Attachment points1102 at one end may be rotated 90 degrees relative to the attachmentpoints 1102 at the opposing end.

Thin-film mesh 1110 having two attachment points 1102 at each endrotated 90 degrees relative to each other as shown in FIG. 11C may beformed by depositing a Nitinol layer 1104 shown in FIG. 11D on an etchedwafer (e.g., Nitinol layer 410 on etched wafer 400 as shown in FIGS. 4Gand 5D) as described above with respect to block 306 of FIG. 3 ,depositing a sacrificial layer (e.g., sacrificial layer 422 as shown inFIGS. 4L and 5E) on Nitinol layer 1122 as described above with respectto block 316 of FIG. 3 , and then depositing a Nitinol layer 1126 shownin FIG. 11E (e.g., Nitinol layer 424 as shown in FIGS. 4N and 5F) on thesacrificial layer 224 and edges of Nitinol layer 1122 as described abovewith respect to block 320 of FIG. 3 . Alternatively, Nitinol layer 1122and Nitinol layer 1126 may be fabricated on separate wafers and joinedat the long/longitudinal edges thereafter.

FIG. 11F is a diagrammatic side elevational view of thin-film meshdevice 1120 including thin-film mesh 1110 attached to backbone 122 atone or more attachment points/areas 1102. Attachment using one or moreattachment points/areas 1102 advantageously confers flexibility tothin-film mesh device 1120. Because blood vessels in the body are oftencurved and not straight, thin-film mesh device 1120 may be bent around acurvature of a blood vessel. The problem of keeping thin-film mesh 1110in place on backbone 122 when thin-film mesh device 1120 is bent intortuous blood vessels is resolved by attaching thin-film mesh 1110 thatis flexible to stent backbone 122/722 using attachment points/areas1102.

As shown in FIG. 11G, when thin-film mesh device 1120 is bent, thin-filmmesh 1110 is held in place by attachment points/areas 1102. Thin-filmmesh 1110 may have an angle 1122 at or near attachment point 1102 whennot bent around a curve (as shown in FIG. 11F) and an angle 1124 smallerthan angle 1122 at or near attachment point 1102 when thin-film mesh1110 is bent around a curve (as shown in FIG. 11G) as thin-film mesh1110 is expanded longitudinally along backbone 122 and narrowedlaterally due to the curvature. The state of expansion of thin-film mesh1110 in FIG. 11G may be an intermediate expanded state, which may be inbetween thin-film mesh 1100 as shown in FIG. 11A (unexpanded state) andthin-film mesh 1110 as shown in FIG. 11B (fully expanded state).

FIGS. 12A-D show diagrammatic close-up views of attachment points/areas1102 of thin-film meshes 1110. In some embodiments, attachmentpoint/area 1102 includes two holes 1202 at attachment point/area 1102 asshown in FIG. 12A. Thin-film mesh 1110 may be attached to backbone 122at attachment point/area 1102 using a wire or thread 1204 that is placedthrough holes 1202 and around backbone 122, as shown in FIG. 12B. Wireor thread 1204 may be a metal wire, such as a gold wire that may alsofunction as a radiopaque marker, or a polymer thread, such as polymerthreads used for sutures. In other embodiments, attachment point/area1102 may be an area for wrapping around backbone 122 as shown in FIG.12C. Wire or thread 1204 may be used to wrap around attachmentpoint/area 1102 as shown in FIG. 12D. In further embodiments, a soldermay be used to attach thin-film mesh 1110 onto backbone 122.

FIGS. 13A-B are diagrammatic flat-pattern views of kink-resistant stentbackbones 1322 (e.g., backbone 122 in FIGS. 1C-1D and 2D). Flat patternviews are how stent backbones 1322 would look if sliced along thelongitudinal direction and opened flattened (i.e., in itsthree-dimensional cylindrical form, the left ends are joined to theright ends). Stent backbones 1322 have “chain-link” fence patternsincluding diamond-shaped fenestrations 1302 and heart-shaped/V-shapedfenestrations 1304. It will be appreciated that stent backbones 1322including fenestrations of other shapes may be used in alternativeembodiments. A thin-film mesh device (e.g., thin-film mesh device 120 inFIG. 1C) that includes a thin-film mesh (e.g., thin-film mesh 110 inFIG. 1B) attached to stent backbone 1322 is advantageouslykink-resistant and flexible. Accordingly, kink-resistant stent backbone1322 may be structured to optimally interact with thin-film mesh 110 andfurther utilize the advantageous features of thin-film mesh 110.

FIG. 14 is a flow diagram of a process 1400 to insert a modularthin-film mesh stent device 1520 including at least two thin-film meshstent modules 1522, 1526 at a site including a bifurcated aneurysm 1532(e.g., an intracranial aneurysm at a vessel bifurcation) as shown inFIGS. 15A-C. At block 1402, thin-film mesh stent module 1522 is insertedsuch that it extends from blood vessel 1534 to one side of bifurcationsuch as blood vessel 1536, as shown in FIG. 15A. Thin-film mesh stentmodule 1522 may include thin-film mesh 110 over a stent backbone 1524.Stent backbone 1524 may have a low percent metal coverage (e.g.,approximately 8% or less). Stent backbone 1524 may be designed withfenestrations that are large and open to accommodate modular stenting.Alternatively, stent backbone 1524 may be designed with a large opensection or hole in the middle to accommodate modular stenting.

At block 1404, a penetrating wire 1540 is used to make a hole/opening1542 in thin-film mesh 110 on thin-film mesh stent module 1522, as shownin FIG. 15B. Penetrating wire 1540 may be configured to facilitatesmooth penetration of thin-film mesh 110. For example, penetrating wire1540 may have a tip 1544 that is sharp or a barbed structure close totip 1544.

At block 1406, thin-film mesh stent module 1526 may be placed throughhole 1542 on thin-film mesh stent module 1522 such that it extends fromblood vessel 1534 to the other side of bifurcation such as blood vessel1538, as shown in FIG. 15C. Thin-film mesh stent module 1526 may includethin-film mesh 110 over a stent backbone 1528. Thin-film mesh stentmodule 1526 may be configured to effectively interact with thin-filmmesh stent module 1522. For example, thin-film mesh stent module 1526may be tapered or flared at one or both ends to fit hole/opening 1542 onthin-film mesh stent module 1522. In another example, stent backbone1528 may only be partially covered with thin-film mesh 110 (e.g., thedistal portion of stent backbone 1528) so that the portion of thin-filmmesh stent module 1526 inside thin-film mesh stent module 1522 is notcovered with thin-film mesh 110 to avoid overlap of thin-film mesh 110.

Treating bifurcated aneurysm 1532 using modular thin-film mesh stentdevice 1520 avoids problems faced in conventional techniques. Forexample, conventional Y-stenting techniques are unsatisfactory becausethey involve placing two stents in a single parent vessel. Further,intrasaccular therapies that involve placing a spherical mesh structureinside an aneurysm have numerous disadvantages, such as the sphericalmesh being difficult to size properly and requiring a physician to enterand manipulate the fragile aneurysm sac. Modular thin-film mesh stentdevice 1520 is a more effective device, as it does not require placingtwo stents in the parent vessel—there is only one opening at bloodvessel 1534 once modular thin-film mesh stent device 1520 is formed bycombing two modules 1522 and 1526, and modular thin-film mesh stentdevice 1520 does not require sizing or manipulating of the fragileaneurysm sac.

FIGS. 16A-E show illustrative micropatterned shapes (e.g., fractal,fractal-like, or other complex micropatterns) that may be implemented aspore edges or pore shapes for pores/fenestrations (e.g.,pores/fenestrations 112) of a thin-film mesh such as thin-film mesh 110.A challenge in tissue engineering is establishing a three-dimensionalstructure in a desired shape that can serve as a scaffold for cellularin-growth. Thin-film mesh 110 (e.g., a TFN mesh) can serve as such amaterial by (1) being covered with a fibrinous layer derived from bloodproducts (including fibrin and platelets) when placed in flowing bloodand (2) by the in-growth of endothelial cells from adjacent endogenoustissue (seeding process). The ability of the cells to grow onto thisfibrinous layer and for the layer to be formed depends upon particularcharacteristics of thin-film mesh 110. When blood is flowing over orthrough a piece of thin-film mesh 110 that has porosities patterned intoit, a greater cumulative edge length of the pores leads to greatercellular in-growth.

In one or more embodiments, pores are formed with fractal micropatternsto provide maximized edge length while minimizing any reduction in thepore area. Conventionally, pores have been patterned with simplegeometries, such as squares or parallelograms. Fractals are geometricshapes that exhibit the property of self-similarity at different scales;examples include the Koch Snowflake, Gosper Island, and Sierpinskisieve. In contrast to the simpler geometric patterns previouslyemployed, there is a clear advantage to using pores that employ complex,fractal, or fractal-like micropatterning of thin-film mesh 110. Thesegeometries serve to advantageously increase the edge length of thepores, as the cumulative edge length per unit of area is a determinantof successful deposition of a fibrinous layer and the growth of aphysiologic-like layer of cells.

The pore edges (e.g., the struts formed by thin-film mesh 110 aroundeach pore) of thin-film mesh 110 may have no complex, fractal, orfractal-like micropatterns as shown in FIG. 16A, or may have complex,fractal, or fractal-like micropatterns as shown in FIGS. 16B-E. Theseare intended to be examples, and other specific configurations may beapparent to one skilled in the art. In FIG. 16A, the pore is a simplesquare shape with straight line edges. In FIG. 16B, the edges of thepore have been made more complex with dentaling or tooth-likemodifications, which increases edge length. In FIG. 16C, a simplefractal-generation rule has been applied, in that the middle section ofeach line segment is displaced into the central area of the pore, whichalso increases edge length. FIGS. 16D and 16E are example refinements ofthe pores in FIGS. 16B and 16C, with the patterns becoming increasinglycomplex and the edge length increased. Different applications may bebest suited by different balances between increases in edge length anddecreases in pore area. Examples of values for FIGS. 16A-E are shown inthe table below.

Configuration: FIG. FIG. FIG. FIG. FIG. 16A 16B 16C 16D 16E Area 441 401405 301 333 Normalized Area 1.000 0.909 0.918 0.683 0.755 Edge Length 84156 108 300 236 Normalized Edge 1.000 1.857 1.286 3.571 2.810 LengthNormalized Edge 1.000 2.042 1.400 5.233 3.721 Length/Normalized Area

In some embodiments, thin-film mesh 110 with complex, fractal, orfractal-like micropatterned pores may be used as a thin-film mesh coverfor a stent device. A complex, fractal, or fractal-like micropattern maybe etched on a silicon wafer. For example, grooves or trenches (e.g.,trenches 406 in FIG. 4E or 5C) may be etched on the wafer according tothe complex, fractal, or fractal-like micropattern as described abovewith respect to block 302 of FIG. 3 . Using the etched wafer, thethin-film mesh cover with the complex, fractal, or fractal-likemicropatterned pores may be formed as described above with respect toblocks 304-326 of FIG. 3 . The micropatterned thin-film mesh may or maynot require expanding to open up fenestrations as described above withrespect to block 328 of FIG. 3 depending on whether the fenestrationsare fabricated as slits to be opened up or as pores that do not requireexpansion. Micropatterned thin-film mesh 110 may be shaped to itsthree-dimensional form (e.g., a cylindrical tube) and then assembled ona backbone or a scaffold (e.g., a stent backbone) such as backbone 122.The characteristics of the micropattern may be selected to ensure thecorrect balance between edge length and pore area, and to ensureproviding the appropriate elasticity to thin-film mesh 110. The complex,fractal, or fractal-like geometry provides greater edge length for eachpore with little or no reduction in pore size. Advantageously, thegreater edge length promotes fibrin binding and cell growth (e.g.,endothelialization) while still allowing blood flow through the pore, asthe pore size is not significantly reduced.

FIG. 17 shows a flow diagram of a process to fabricate a thin-film meshsuch as thin-film mesh 110 for a thin-film mesh device (e.g., athin-film mesh scaffold device) such as thin-film mesh device 120 fortissue-engineering. Thin-film mesh device 120 may be composed of orinclude thin-film mesh 110 that is a thin-film mesh membrane (e.g., aTFN membrane), a three-dimensional (3D) thin-film mesh structure (e.g.,a 3D TFN structure), or other thin-film mesh structure. In someembodiments, thin-film mesh 110 may have diamond-shaped pores as shownin FIG. 1B or 7A-C. In some embodiments, thin-film mesh 110 may includepores with complex, fractal, or fractal-like pre edges or pore shapes asshown in FIGS. 11B-E.

At block 1702 a micropattern is etched on a wafer (e.g., as described inrelation to block 302 of FIG. 3 ). In some embodiments, a complex,fractal, or fractal-like micropattern according to FIGS. 11B-E is etchedon the wafer. For example, grooves or trenches (e.g., trenches 406 inFIG. 4E or 5C) may be etched according to the complex, fractal, orfractal-like micropattern using a deep reactive ion etching (DRIE)process.

At block 1704, a layer of Nitinol (e.g., e.g., Nitinol layer 410 asshown in FIGS. 4G and 5D) is sputter-deposited on the wafer to form athin-film mesh on the wafer (e.g., as described with respect to block306 of FIG. 3 ). In some embodiments, one or more sacrificial layers(e.g., sacrificial layer 422 as shown in FIGS. 4L and 5E) and one ormore additional layers of Nitinol (e.g., Nitinol layer 424 as shown inFIGS. 4N and 5F) may be deposited (e.g., as described above with respectto block 316 and block 320 in FIG. 3 ) depending on thethree-dimensional shape of thin-film mesh 110 that is desired. In someembodiments, the layer of Nitinol is sputter-deposited on the complex,fractal, or fractal-like micropatterned grooves of the wafer. Thecomplex, fractal, or fractal-like micropattern of grooves is duplicatedon the resulting thin-film mesh as complex, fractal, or fractal-likemicropatterned fenestrations.

At block 1706, the thin-film mesh is removed from the wafer (e.g., asdescribed with respect to block 326 in FIG. 3 ).

At block 1708, macroscopic features are created by shaping thin-filmmesh 110 to the desired form to form thin-film mesh device 120 to serveas a scaffold for tissue engineering. Thin-film mesh 110 may be shapedvia stamping, wrapping thin-film mesh 110 over a forming apparatus(e.g., a mold), or vacuum forming over a forming apparatus with a layerof plastic placed over thin-film mesh scaffold 110. In some embodiments,thin-film mesh device 120 further includes a backbone such as backbone122 for support or to deliver thin-film mesh 110.

At block 1710, the shaped thin-film mesh scaffold 110 is removed fromthe forming apparatus and extracellular matrix components (e.g.,collagen, elastin, fibronectin, laminin, and/or other extracellularmatrix components) or other biomolecules may be provided on thin-filmmesh scaffold device 120. Thin-film mesh scaffold device 120 is therebyconfigured to promote cell growth while simultaneously achievingadvantageous mechanical properties and allowing for cell migration andexchange of nutrients and information.

In one or more embodiments, thin-film mesh scaffold device 120 is placedin a fluid (e.g., a solution including extracellular matrix componentsor other biomolecules) such that a fibrinous layer of coagulatedmaterial is deposited on thin-film mesh 110. In an example, the fluidmay be a blood-based fluid such as blood plasma, blood serum, or otherblood-based fluid. The fluid may contain fibrin, fibrinogen, clottingfactors, and/or other components of whole blood, but may exclude redblood cells and white blood cells. In some embodiments, the fluid may bepassed over thin-film mesh scaffold device 120 to deposit the fibrinouslayer of coagulated materials. In other embodiments, thin-film meshscaffold device 120 is coated with extracellular matrix components orother biomolecules.

At block 1712, the fibrinous layer on thin-film mesh scaffold device 120is seeded with cells selected to be compatible with the individual forwhom the engineered tissue is being prepared. For example, the fibrinouslayer may be seeded with epithelial cells, endothelial cells, or stemcells (e.g., pluripotent stem cells). Thin-film mesh scaffold device 120may then be bathed in a fluid containing growth factors selected tomatch the cells that were seeded and induce the cells to grow into thetype of tissue desired.

Thin-film mesh scaffold device 120 formed via blocks 1702-1712 is aparticularly advantageous platform for tissue engineering and cellgrowth. Thin-film mesh scaffold device 120 may have pores of any shapewith a pore size between 1 mm and 5 μm, or even less using more advancedlithography techniques such as electron beam writing. Such pores allowfor intercellular communication, nutrient exchange, fluid flow, andmovement. Thin-film mesh scaffold device 120 is strong and at the sametime malleable, in contrast to conventional cell scaffold devicescomposed of or including hydrogels, fibrin based gels, and electrospunpolymers that are too brittle or too malleable. Thus, conventional cellscaffold devices fail to achieve the desired conformation, strength, andcontrolled porosity of thin-film mesh scaffold device 120. Moreover,conventional scaffold devices also suffer from the inability to engineerexact pore configurations and instead rely on a random distribution ofpores. Further, thin-film scaffold device 120 may be composed of orinclude TFN which, as a shape memory alloy, returns to its formed shapeeven after significant mechanical distortion. Gels, polymers, and mostother materials do not share this property.

In some embodiments, thin-film mesh scaffold device 120 may be used inconjunction with biological substrates to facilitate rapid cellularin-growth of the tissue engineering construct. Thin-film mesh scaffolddevice 120 with the addition of biological substrates may be referred toas a hybrid scaffold or hybrid membrane. For example, thin-film meshscaffold device 120 may be incubated with whole blood, plasma, plateletrich plasma, platelet rich fibrin, platelet poor fibrin, collagensolutions, or solutions of other extracellular matrix proteins to createa hybrid scaffold, which may be used for cell growth and tissueengineering. The biological components of the hybrid scaffold facilitaterapid cellular ingrowth of the construct (either in vitro or in vivo)while thin-film mesh 110 and/or backbone 122 provides the structure fortissue ingrowth and interaction between cells on the construct or withcells of the host organism receiving the construct.

In some embodiments, thin-film mesh scaffold device 120 may be annealedin the desired anatomical configuration prior to seeding with thebiological components. As thin-film mesh scaffold device 120 isexceptionally malleable, thin-film mesh scaffold device 120 may beannealed in virtually any shape to facilitate interaction with the hosttissue and/or to position cells in advantageous configurations that willfacilitate intercellular interactions. Because of the shape memoryproperties of thin-film mesh scaffold device 120, it will return to thegiven shape even after forces transiently distort it.

FIG. 18 is a diagrammatic perspective view of a multi-layered thin-filmmesh membrane 1802 that may be used, for example, to create a tissueengineered vascular graft (TEVG) 1800. Multi-layered thin-film meshmembrane 1802 may include an inner thin-film mesh cylinder 1804 and anouter thin-film mesh cylinder 1806. Multi-layered thin-film meshmembrane 1802 may further include one or more intermediate thin-filmmesh cylinders (not shown in FIG. 18 ). Inner thin-film mesh cylinder1804 includes a tubular micropatterned thin-film mesh, which may havemechanical properties similar to the inner elastic layer of a vesselwall (e.g., the internal elastic lamina). Outer thin-film mesh cylinder1806 includes another tubular micropatterned thin-film mesh, which mayhave mechanical properties that are similar to the outer elastic layerof a vessel wall (e.g., the external elastic lamina). Inner thin-filmmesh cylinder 1804 and outer thin-film mesh cylinder 1806 may be formed,for example, using the process described above with respect to FIG. 3 .

Inner thin-film mesh cylinder 1804 and outer thin-film mesh cylinder1806 may be incubated with biomolecules to form hybrid inner and outermembranes prior to, or concurrently with, seeding cells. Endothelialcells 1808 may be seeded on inner thin-film mesh cylinder 1804 (e.g., onthe inner surface, the outer surface, or both), which may grow togenerate a layer of endothelial cells (e.g., the tunica intima of avessel). Smooth muscle cells 1810 may be seeded between inner thin-filmmesh cylinder 1804 and outer thin-film mesh cylinder 1806, which maygrow to generate smooth muscle tissue (e.g., the tunica media of avessel). Fibroblast cells 1812 may be seeded on the outer thin-film meshcylinder 1806 (e.g., on the inner surface, the outer surface, or both),which may grow to generate connective tissue (e.g., the adventitia of avessel). The seeded multi-layered thin-film mesh membrane 1802 may beincubated to grow the cells and used during a vascular graft procedureon a patient.

FIGS. 19A-B show a double-spiral thin-film mesh membrane 1900 and a 3Ddouble-spiral thin-film mesh structure 1910. As shown in FIG. 19A,double-spiral thin-film mesh membrane 1900 may be flat or substantiallyflat. Alternatively, double-spiral thin-film mesh membrane 1900 may beformed to have a curved shape (e.g., to conform to the shape of a partof the body). Double-spiral thin-film mesh membrane 1900 may be madefrom a layer of thin-film mesh deposited on a silicon wafer. Forexample, grooves may be etched on a silicon wafer according to adouble-spiral shape, a layer of thin-film mesh may be deposited in thegrooves of the wafer to form the double-spiral thin-film mesh membrane1900, and then the double-spiral thin-film mesh membrane 1900 may beremoved from the wafer using a lift-off process (e.g., as describedabove with respect to process 300 in FIG. 3 and process 1700 in FIG. 17).

As shown in FIG. 19B, 3D double-spiral thin-film mesh structure 1910includes a plurality of double-spiral thin-film mesh membranes 1900stacked to create a three-dimensional cell matrix. In some embodiments,3D double-spiral thin-film mesh structure 1910 may be formed from aplurality of double-spiral thin-film mesh membranes 1900 formed with asingle layer of thin-film mesh on a wafer. In other embodiments, 3Ddouble-spiral thin-film mesh structure 1910 may be formed by depositingmultiple layers of thin-film mesh on a wafer separated by multiplelayers of sacrificial layers (e.g., as described above with respect toprocess 300 in FIG. 3 ).

In some embodiments, each of double-spiral thin-film mesh membranes 1900may include a plurality of struts 1902 sized to facilitate cell growth.The struts of 3D double-spiral thin-film mesh structure 1910 may have adensity to facilitate cell growth and provide similar structural and/ormechanical properties as a tissue in the body.

In some embodiments, each of double-spiral thin-film mesh membrane 1900may include a central opening 1904 that forms a central channel 1906through which fluid may flow. For example, a fluid with nutrients mayflow through central channel 1906 and provide nutrients to cells growingin or on 3D double-spiral thin-film mesh structure 1910.

In an example, 3D double-spiral thin-film mesh structure 1910 may beused as a scaffold device for growing a part of a bone, such as anosteon. 3D double-spiral thin-film mesh structure 1910 may be incubatedwith biomolecules to form a hybrid structure prior to, or concurrentlywith, seeding cells. Bone cells (e.g., osteoblasts, osteoclasts, etc.)may be seeded in 3D double-spiral thin-film mesh structure 1910, whichmay grow and deposit calcium to form the osteon. 3D double-spiralthin-film mesh structure 1910 may be used during a bone graft procedureon a patient.

FIGS. 20A-B show a honeycomb thin-film mesh membrane 2000 and a 3Dhoneycomb thin-film mesh structure 2010. As shown in FIG. 20A, honeycombthin-film mesh membrane 2000 may be flat or substantially flat.Alternatively, honeycomb thin-film mesh membrane 2000 may be formed tohave a curved shape (e.g., to conform to the shape of a part of thebody). Honeycomb thin-film mesh membrane 2000 may be made from a layerof thin-film mesh deposited on a silicon wafer. For example, grooves maybe etched on a silicon wafer according to a honeycomb shape, a layer ofthin-film mesh may be deposited in the grooves of the wafer to formhoneycomb thin-film mesh membrane 2000, and honeycomb thin-film meshmembrane 2000 may then be removed from the wafer using a lift-offprocess (e.g., as described above in relation to process 300 in FIG. 3and process 1700 in FIG. 17 ). Advantageously, due to the highlyefficient packing of the honeycomb shape, honeycomb thin-film meshmembrane 2000 provides very low metal to surface area ratio and may beused to grow cells in a variety of tissue engineering applications.

In one example, honeycomb thin-film mesh membrane 2000 may be used forplacement over wounds or damaged tissue. Honeycomb thin-film meshmembrane 2000 may be incubated with biomolecules (e.g., fibrin,collagen, growth factors, etc.) to form a hybrid membrane prior to, orconcurrently with, seeding cells (e.g., stem cells). Honeycomb thin-filmmesh membrane 2000 may then be placed over a wound or damaged tissue orwounds to facilitate healing.

As shown in FIG. 20B, 3D honeycomb thin-film mesh structure 2010includes a plurality of honeycomb thin-film mesh membranes 2000 stackedto create a three-dimensional cell matrix. In some embodiments, 3Dhoneycomb thin-film mesh structure 2010 may be formed from 3D honeycombthin-film mesh structure 2010 formed as a single layer of thin-film meshon a wafer. In other embodiments, 3D honeycomb thin-film mesh structure2010 may be formed by depositing multiple layers of thin-film mesh on awafer separated by a sacrificial layer (e.g., as described above inrelation to process 300 in FIG. 3 ).

In an example, 3D honeycomb thin-film mesh structure 2010 may be used asa scaffold device for guiding cell growth. 3D honeycomb thin-film meshstructure 2010 may be constructed to have a similar structure to a crosssection of a nerve. 3D honeycomb thin-film mesh structure 2010 may beincubated with biomolecules to form a hybrid structure prior to, orconcurrently with, seeding cells. 3D honeycomb thin-film mesh structure2010 may be placed between two ends of a severed nerve to facilitategrowth of nerve cells between the severed nerve.

FIG. 21 shows an equilateral-triangle thin-film mesh membrane 2100.Equilateral-triangle thin-film mesh membrane 2100 may be advantageouslyused for applications in which strong structural/mechanical propertiesare desirable.

FIG. 22 shows an overlapping-circle thin-film mesh membrane 2200.Overlapping-circle thin-film mesh membrane 2200 may have denseconnections, and may be advantageously used for applications in whichstrong structural/mechanical properties along with close packing ofcells are desirable.

FIGS. 23A-B show an amplifier thin-film mesh membrane 2300 denser on oneside/area (e.g., along direction 2302). Amplifier thin-film meshmembrane 2300 may be denser on one side/area by using fractal shapes orfractal-like shapes formed asymmetrically along direction 2302.Amplifier thin-film mesh membrane 2300 may be incubated withbiomolecules (e.g., fibrin, collagen, growth factors, etc.) to form ahybrid membrane prior to, or concurrently with, seeding cells (e.g.,neurons, muscle cells, cardiac myocytes). As shown in FIG. 23B, whencells 2304 are seeded on amplifier thin-film mesh membrane 2300, theremay be progressively more cells 2304 when moving along direction 2302.Advantageously, cells 2304 may be grown and/or organized such that whenstimulus 2306 is provided at one end 2308, one or more signals (e.g.,neural signals) may be passed in direction 2302, for example via paths2310, 2312, and paths in-between 2310 and 2312, thereby providing anamplified output 2314 at the other end 2316.

In various embodiments, flat or curved thin-film mesh membranes havingother shapes may be formed to be used as a scaffold device for tissueengineering. Further, each of the flat thin-film mesh membranes may bestacked to create a 3D thin-film mesh structure that may be used as a 3Dscaffold device for tissue engineering. The flat or curved thin-filmmesh membranes and the 3D thin-film mesh structures may be seeded withcells to generate a cell matrix/construct, and grafted into a patient.

A thin-film mesh membrane (e.g., thin-film mesh membrane 1802, 1900,2000, 2100, 2200, 2300, or other thin-film mesh membrane), a thin-filmmesh structure (e.g., thin-film mesh structure 1910, 2010, or otherthin-film mesh structure), or a corresponding hybrid membrane/structuremay be used for various medical treatments as described below.

In some embodiments, a thin-film mesh membrane, a thin-film meshstructure, or a corresponding hybrid membrane/structure may be used, forexample, for to facilitate wound healing for burns, pressure ulcers,scar revisions, ischemic lower limb ulcers and other acute and chronicwounds.

In some embodiments, a thin-film mesh membrane, a thin-film meshstructure, or a corresponding hybrid membrane/structure may be used tostop acute bleeding whether from injury or from surgical intervention(“hemostasis”).

In some embodiments, a thin-film mesh membrane, a thin-film meshstructure, or a corresponding hybrid membrane/structure may be used tofacilitate bone healing that is wrapped around or placed within afracture site, or is wrapped around structural elements formed of othermaterials (e.g. titanium) that bridge a gap between bones.

In some embodiments, a thin-film mesh membrane, a thin-film meshstructure, or a corresponding hybrid membrane/structure may be used togrow human chondrocytes and create a thin plate of cartilage. Thiscartilage plate could be used in joint operations to delay knee or hipreplacement or other osteoarthritic conditions.

In some embodiments, a thin-film mesh membrane, a thin-film meshstructure, or a corresponding hybrid membrane/structure may be used todeliver chemotherapeutics directly to the site of a tumor followingsurgical excision of the tumor.

In some embodiments, a thin-film mesh membrane, a thin-film meshstructure, or a corresponding hybrid membrane/structure may be used incardiac surgery to place cardiac myocytes at a site of myocardialinfarction. Following infarct the surgeon would excise the scarred areaand insert the membrane or the hybrid membrane to facilitate regrowth ofhealthy tissue as opposed to scar tissue that typically accompaniesmyocardial infarction.

In some embodiments, a thin-film mesh membrane, a thin-film meshstructure, or a corresponding hybrid membrane/structure may be used as ascaffold device for nerve regrowth following injury. The thin-film meshmembrane or hybrid membrane would have channels aligned like a nativenerve to facilitate axon growth in a controlled manner.

In some embodiments, a thin-film mesh membrane, a thin-film meshstructure, or a corresponding hybrid membrane/structure may be used inreconstructive or cosmetic surgery to replace ligaments because of theelastic properties of thin-film mesh (e.g., breast tissue containsmultiple small ligamentous elements that give rise to the shape andmechanical properties of the organ, and post-mastectomy prostheses,i.e., breast implants, are essentially non-structured bags of saline,silicone gel, or other materials).

In some embodiments, thin-film mesh membranes, thin-film meshstructures, and/or corresponding hybrid membranes/structures can bejoined together to create the basis for more complex cartilaginousstructures (e.g., external ear, portions of nose) when seeded withchondrocytes.

In some embodiments, a thin-film mesh membrane, a thin-film meshstructure, or a corresponding hybrid membrane/structure may be used toreplace elements of the eye that have been injured traumatically or bydisease (e.g., a tumor).

In some embodiments, a thin-film mesh membrane, a thin-film meshstructure, or a corresponding hybrid membrane/structure may be used toconstruct replacement elements of the bronchial tree in the lungs.

In some embodiments, a thin-film mesh membrane, a thin-film meshstructure, or a corresponding hybrid membrane/structure composed of orincluding Nitinol may be seeded with myocytes to construct replacementskeletal muscle. Because Nitinol has the ability to change shape whenelectrical current is passed through it, it may be advantageously beused in artificial limbs.

In some embodiments, a thin-film mesh membrane, a thin-film meshstructure, or a corresponding hybrid membrane/structure may be used as ameans to deliver both small and large molecules (i.e. proteins) toanatomical sites of interest.

Embodiments described herein illustrate but do not limit the disclosure.It should also be understood that numerous modifications and variationsare possible in accordance with the principles of the presentdisclosure. Accordingly, the scope of the disclosure is best definedonly by the following claims.

What is claimed is:
 1. A method comprising: forming a metallic thin filmon a substrate by sputter deposition; forming fenestrations in themetallic thin film based on micropatterns provided on the substrate;placing the metallic thin film in a solution to form structural proteinson the metallic thin film.
 2. The method of claim 1, further comprisingexpanding the metallic thin film to open up the fenestrations, such thatthe metallic thin film has a pore density of between 65 and 1075 poresper mm² and a percent area coverage of between 16 and 66%;
 3. The methodof claim 1, wherein the fenestrations form a fractal-like micropattern.4. The method of claim 1, further comprising adding one or more smallmolecules or large molecules to the metallic thin film or the structuralproteins configured to achieve a desired therapeutic effect at ananatomic site of interest where the metallic thin film is to bedeployed.
 5. The method of claim 1, further comprising: deep reactiveion etching a micropattern of trenches on a surface of the substrate,the trenches corresponding to the fenestrations of the metallicthin-film; depositing a lift-off layer on the etched substrate;depositing a first Nitinol layer over the lift-off layer; and etchingthe lift-off layer to form the metallic thin film.
 6. The method ofclaim 5, further comprising: depositing a bonding layer on at least onearea of the first Nitinol layer; depositing a sacrificial layer on aremaining area of the first Nitinol layer; depositing a second Nitinollayer on the bonding layer and the sacrificial layer; and annealing thefirst Nitinol layer and the second Nitinol layer with the bonding layer;wherein the etching further etches the sacrificial layer to form athree-dimensional, metallic thin film micromesh.
 7. The method of claim1, further comprising: forming a plurality of metallic thin films;placing the plurality of metallic thin films in one or more solutions toform structural proteins on the plurality of metallic thin films; andstacking the plurality of metallic thin films to form athree-dimensional thin-film micromesh structure.
 8. The method of claim1, further comprising: forming a plurality of metallic thin films;forming an inner and an outer thin-film mesh cylinders from theplurality of metallic thin films; placing the inner and the outerthin-film mesh cylinders in one or more solutions to form structuralproteins on the inner and the outer thin-film mesh cylinders; andenclosing the inner thin-film mesh cylinder in the outer thin-film meshcylinder to form a multi-layer thin-film mesh cylinder structure.
 9. Themethod of claim 1, further comprising: seeding the metallic thin filmwith cells; and incubating the metallic thin film to promote cellgrowth.
 10. The method of claim 1, further comprising: placing themetallic thin film over a backbone to form a cylindrical tube; andattaching the metallic thin film to the backbone.